Although a large number of specific therapeutic agents are available for treatment of patients with cardiovascular disease, most of these drugs have never been rigorously tested in clinical trials conducted in infants and children with heart disease. Testing in the pediatric population has been included relatively recently as a requirement for gaining Food and Drug Administration approval for a new drug. Even so, most drugs currently used to treat infants with cardiac conditions have not been evaluated with respect to pharmacokinetics, efficacy, or safety in this population.

The number of drugs available to treat cardiovascular disorders is enormous. Rather than attempting to maintain extensive knowledge about each specific drug, it is much more practical to understand principles and mechanisms of action according to drug classification. Practical differences among drugs within a given class are often of minimal clinical significance. A useful approach is to understand general mechanisms of action and to become familiar with one or two specific agents within a given class. In this manner, a small “personal” formulary can be developed that greatly simplifies the amount of information necessary to provide appropriate therapy. It is also important to stay current, be alert to new drug developments, and be willing to modify the approach to drug therapy as new information becomes available.

Drug therapy in infants should be founded on sound principles of clinical pharmacology. Ideally, drug administration is justified only if sufficient data exist to indicate that the overall morbidity or mortality of the disease is reduced by therapy and the beneficial effects outweigh the adverse drug effects. However, information regarding basic and clinical pharmacology of many drugs is simply not available in the neonatal population. Drug therapy for infants with cardiovascular disease is therefore usually extrapolated from studies performed in adult patients or older children and is often guided by personal experience, anecdotal reports, tradition, or uncritical acceptance of drug advertising. Medications are often administered on the basis of personal belief that a drug is effective, sometimes even in the face of scientific evidence to the contrary.

The general concept of rational drug therapy (Table 12-1) is to prescribe drugs in an attempt to maximize efficacy and to minimize adverse drug effects. This implies that therapy is tailored to the needs of a particular patient and clinical situation. Nowhere is this more important than in the newborn population. Adverse or toxic effects of a drug in neonates may not become clear until the drug has been marketed for many years. Even though a drug is commercially available and has been used in adults, it may not be safe or effective in a newborn with heart disease.

Adherence to the general features of rational drug therapy, which avoids prescribing on the basis of personal beliefs, will most certainly improve use of medications. A firm understanding of the pathophysiology of the disease being treated is also necessary to provide effective drug therapy, so it is important to make every attempt to establish a diagnosis with certainty.

Application of drug therapy to a specific neonatal patient should be considered a “therapeutic experiment.” Even if specific information regarding the pharmacology, pharmacodynamics, and pharmacokinetics of a particular drug is available for neonates, an individual patient may not have been exposed to the specific chemical entity to be administered. Furthermore, although the drug may have been tested in neonates with other conditions, the underlying pathophysiology and genetic makeup of a specific patient may affect the response to the medication. If drug administration is approached as a therapeutic experiment in every patient, a heightened awareness of drug efficacy and toxicity is generated. It is imperative to set end points of therapy, to monitor appropriately for such end points, and to observe carefully for adverse drug effects. The approach to rational and age-appropriate drug therapy must be based on a firm understanding of drug metabolism, distribution, receptor/effector ontogeny, and knowledge of the molecular and cellular processes involved in regulation of cardiovascular function in preterm and term neonates.

Pharmacokinetics defines drug concentrations in mathematical and kinetic terms. Absorption, distribution, metabolism, and excretion all affect the pharmacokinetic profile of a particular drug. Each of these processes can be described in quantitative terms. These principles are especially useful if the pharmacodynamic effects of a particular drug can be related to the concentration of the drug. Fortunately, for most drugs, a close relationship exists between the pharmacodynamic action of the drug and the concentration of the drug at the receptor site of action. Thus, understanding the various factors that influence the overall pharmacokinetic profile of a given drug is important in developing a rational and age-appropriate therapeutic strategy.

Absorption

Drugs are administered by intravenous infusion or by extravascular routes (orally, sublingually, intramuscularly, subcutaneously, rectally, or by inhalation). For extravascular routes of administration, the drug must be absorbed across cell membranes to reach the bloodstream, where distribution subsequently occurs. In selected cases, inhalational therapy provides a high concentration of the drug at the site of action in the lungs (eg, nitric oxide therapy). Most drugs move through membranes by passive diffusion, and therefore drug movement is regulated by the physicochemical properties of the drug, membrane characteristics, pH, and local blood flow.

Drug absorption following intramuscular injection is generally erratic and less reliable than other routes. Perfusion and blood flow to muscle beds is variable and may change rapidly, especially in critically ill newborns. Neonates and preterm infants have relatively little muscle mass, making injection technically difficult. Furthermore, many drugs are insufficiently soluble and are not amenable to intramuscular administration. Thus, intramuscular injections in neonates should be avoided. On the other hand, subcutaneous injection of drugs such as enoxaparin is becoming more common in neonates.

Gastrointestinal Absorption

Diffusion largely drives drug absorption from the gastrointestinal tract. The rate and extent of drug absorption are therefore influenced by gastrointestinal motility, absorptive surface area, pH (which affects ionization of the drug), and gastrointestinal contents. Developmental changes in gastrointestinal characteristics include a relatively greater gastrointestinal surface area (relative to body size), higher gastric pH, delayed gastrointestinal transit time, and the presence of β glucuronidase in the intestinal lumen. Despite important differences in gastrointestinal function, few controlled studies of oral drug bioavailability in neonates are available. A relatively higher gastric pH will reduce the absorption of enterally administered drugs that are poorly ionized. In contrast, the relatively larger surface area of the newborn gastrointestinal tract may potentially increase absorption of many drugs. Gastric emptying and intestinal transit times are often reduced in newborns, especially those with cardiovascular disease who intermittently may have impaired intestinal perfusion. For these reasons, drug absorption varies considerably not only among different patients but even within the same patient at different times.

In addition, drug-metabolizing enzymes and transporters in the intestine can affect the bioavailability of a number of drugs administered orally. Many of these enzymes undergo developmental changes in expression and activity. For example, intestinal expression of CYP3A and CYP1A1 is low at birth and increases with increasing age. The reduced activity at birth results in lower clearance of substrates for these enzymes and higher plasma concentrations of the active compound. Examples of drugs that are metabolized by these pathways include alprazolam, amlodipine, and dexamethasone.

Drug Distribution

Distribution refers to the processes involved in partitioning of a drug among the various body tissues and organs. In general, the movements of drugs throughout tissues are reversible from one location to another and are affected by relative concentrations of the drug at various sites. Drug concentrations in various compartments are in turn determined by many factors, including blood flow, physicochemical properties of the drug, pH, composition of body fluids and tissues, drug binding in the plasma, and drug binding to other tissue proteins. The route of administration is an important determinant of drug distribution, especially in the early phases after administration. Following oral administration, the liver is the first major organ to encounter a drug, whereas the heart and lungs will receive the greatest initial concentration of a drug administered intravenously. The free drug concentration is generally the most reliable determinant of the concentration of the drug at the receptor sites. Therefore, binding to plasma proteins can be an important factor in modulating drug distribution, dose–response relationships, and drug clearance. In general, fundamental age-related differences in the composition of the proteins involved in drug binding diminish binding of drugs to plasma proteins in newborns compared with adults.

Body Composition

Important changes in body composition occur during development that may have profound effects on drug distribution. In a normal full term infant, total body water makes up approximately 75% to 80% of body weight. After birth, there is a rapid fall in total body water and a relative increase in intracellular fluid. By 1 year of age, total body water makes up approximately 60% of body weight. Fat tissue represents only approximately 3% of total body weight in a 28 week gestation premature infant, in contrast to 15% to 28% of the body weight as fat in a term newborn. In newborns, especially premature newborns, the relatively greater proportion of total body water and the lower total body fat content undoubtedly affect the apparent volume of distribution of many drugs.

Apparent volume of distribution is the theoretical volume of fluid into which the total amount of drug administered would have to be diluted to produce the resulting concentration in the plasma. Apparent volume of distribution is influenced by a number of patient variables (including regional perfusion, distribution of fat, muscle and body water, and cell permeability) and drug variables (including protein binding and lipid and water solubility). Many commonly used drugs have a larger apparent volume of distribution in premature and newborn infants (eg, furosemide, theophylline, and aminoglycosides). This becomes especially important when a loading dose is administered since the volume of distribution is a major determinant of an appropriate loading dose.

Metabolism

The two major categories of metabolic or biotransformation reactions are the nonsynthetic (phase I) reactions, such as oxidation, reduction, or hydrolysis, and the synthetic (phase II) reactions, such as sulfation or glucuronidation. Phase I reactions often are followed by a phase II reaction. These processes increase the water solubility of a drug and promote clearance. Most drug metabolism occurs in the liver, but other organs and tissues can contribute significantly to drug metabolism (blood, lungs, gastrointestinal tract, and kidneys). In addition to facilitating more rapid drug clearance, biotransformation may result in either toxic or therapeutically active metabolites. Hepatic metabolism is generally reduced in newborns compared with adults, but this does not uniformly apply to all drugs. In the neonatal period, most phase l and phase II reaction rates are diminished and are more readily saturated. As a result, neonates generally exhibit reduced clearance rates and longer half lives for drugs that are eliminated by biotransformation. However, drug metabolism may change rapidly in the first few months after birth, necessitating appropriate dosage adjustments. Table 12-2 highlights selected aspects of neonatal drug metabolism.

Some drugs, such as angiotensin-converting enzyme inhibitors, are administered in the form of a prodrug. Prodrugs are inactive dosage forms (usually salts or esters) that must be hydrolyzed to release the active form of the drug. Hydrolysis and esterase activity may be quite variable in newborns. Relatively little information is currently available regarding the potential impact of age related differences in de-esterification.

Excretion

Renal excretion is the major pathway for the elimination of most drugs and drug metabolites. Maturation of renal function is well characterized, and much of it occurs after birth. Changes in renal function that occur with gestational age, chronological age, and underlying disease state must be considered for every drug that is eliminated principally via the kidneys. Since congenital heart disease may be associated with reduced renal perfusion, renal function must be monitored in these patients.

Pharmacogenomics

Developmental pharmacogenomics involves both development and genetic constitution as determinants of drug disposition and/or drug response. In adults, genotype–phenotype relationships are largely constant. In contrast, during the perinatal period, numerous processes affecting either pharmacokinetics (eg, drug-metabolizing enzymes and transporters) or pharmacodynamics (eg, receptor expression and signal transduction) are developmentally regulated and undergo changes in expression and activity. This adds further complexity to the genotype–phenotype relationship.

Defining the developmental expression and functional activity of genes involved in determining drug responses is essential for understanding the genotype–phenotype relationship. This is an emerging field, and the effect of normal and abnormal ontogeny on the genotype–phenotype relationships for drug-metabolizing enzymes, transporters, and/or receptor expression has not been investigated during development. If genotype and phenotype are concordant, genotyping can theoretically be used to predict the activity of a drug-metabolizing enzyme or transporter (ie, the phenotype). This has been demonstrated for the cytochrome P450 enzyme, CYP2D6, for which an “activity score” predictive of enzyme activity was constructed following consideration of over 25 different allelic variants and their functional consequences. The potential clinical utility of genotype-derived activity scores will be realized if the score can be shown to predict drug clearance.

Developmental changes in the functional capacity of drug-metabolizing enzymes and transporters are not the only variables affecting the genotype–phenotype relationship. Evidence continues to emerge regarding the impact of the changing intestinal microbiome on drug absorption, metabolism, and regulation of enzyme and transporter expression. For example, breast milk has a different effect on the developmental acquisition of CYP1A2 activity than does formula. Additional investigation is needed to provide further insights into postnatal changes in drug responses. Such insights are essential in order to improve the precision with which drugs are administered to newborns and infants with cardiovascular diseases.

Rational use of therapeutic drug monitoring can be very helpful in adjusting drug dosing, especially in critically ill newborns. The capability to measure the plasma concentration of the most commonly used drugs is widely available. However, a clear relationship between the plasma drug concentration and the pharmacodynamic or toxic effects must be present to provide maximal benefit.

Although guidelines are available for “therapeutic” drug concentrations for many cardiovascular drugs, these values are derived largely from adult population studies. An individual infant may be more or less sensitive to the therapeutic and toxic effects of a specific drug. Some patients will obtain a beneficial effect at steady state plasma concentrations lower than the therapeutic threshold listed by the laboratory. In these cases, increasing the dosage simply to achieve a laboratory value within the therapeutic range is not necessary and could be harmful. Conversely, maintaining a higher-than-usual steady state plasma concentration to achieve efficacy is acceptable if toxicity is absent. Therapeutic drug monitoring is especially useful for antiarrhythmic drugs in complex patients, critically ill patients receiving multiple drugs, or infants with impaired renal and/or hepatic function.

Biomarkers are biological molecules that serve as a sign or signal of a normal or abnormal process associated with a given disease or condition. The National Institutes of Health defines a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or pharmacologic responses to a therapeutic intervention.” Given the difficulties in correlating pharmacokinetics with pharmacodynamics in neonates, measurement of a biomarker to assess the impact of both disease and development on drug responses (including toxicity) in neonatal patients holds great promise.

However, in contrast to studies in adults where multiple biomarkers have been validated and are increasingly used to support drug development, relatively little information is available for pediatric patients. Children have been called “biomarker orphans” because of the challenges in biomarker development in this population, including the need for invasive and repeated sampling, the lack of disease burden relative to adults, and the potential impact of developmental changes per se on a given biomarker. Examples of this latter challenge include understanding how the ontogeny of renal function influences biomarkers used to assess renal injury (eg, NGAL and KIM-1), developmental differences in disease expression, and age-dependent differences in the activity of drug-metabolizing enzymes used as biomarkers to predict drug clearance.

Despite the overall lag in biomarker development for infants and children, some progress has been made recently. For example, protein or peptide biomarkers are being used in a variety of pediatric diseases, including cancer, asthma, biliary atresia, bronchopulmonary dysplasia, nephrotic syndrome, acute renal injury, traumatic brain injury, juvenile idiopathic arthritis, and eosinophilic gastroduodenititis. Although work is ongoing, practical application of biomarkers is very limited in neonates with cardiovascular diseases.

Drug interactions represent an often-neglected source of potential morbidity. In contrast to adult patients with multiorgan system diseases and multiple-drug therapies, neonates are generally managed with a limited number of medications. However, potential adverse drug interactions exist among the most commonly used cardiovascular drugs in newborns. Table 12-3 lists some of the most commonly used cardiovascular drugs in the neonatal period and the clinically relevant drug–drug interactions that might occur with their use. This is a selected and limited listing. Additional references should be consulted when using other drug combinations. Many hospital pharmacies automatically survey for potential drug interactions, but even if they do not, hospital pharmacists are generally an excellent source of information regarding drug interactions.

As understanding of the cellular and molecular aspects of cardiovascular diseases in adult patients has increased, cardiovascular drug therapy has expanded considerably in the past few decades. Many drugs are marketed for the treatment of heart failure and hypertension. In contrast, far less attention has been directed toward the immature heart and cardiovascular system. Although there are relatively few developmental studies, in almost every study published to date, drugs developed for adults affect contractile function in a qualitatively or quantitatively different fashion in immature myocardium. As described in Chapter 2, the fundamental processes involved in contraction, relaxation, and calcium regulation undergo maturational changes in the perinatal period. Important age-related differences exist in virtually all of the cellular components and signaling pathways that are involved in the mechanism(s) of action of conventional pharmacological agents. As a result, the responses to these drugs in the immature cardiovascular system are often poorly understood and may be unpredictable and suboptimal.

This chapter presents an overview of drugs that are most commonly used to treat cardiovascular diseases in neonates. Emphasis is on the management of heart failure since acute and compensated heart failure are common problems in this patient population. Dosage guidelines for commonly used cardiovascular drugs are presented in Table 12-4. Antiarrhythmic agents are discussed in Chapter 10.

The three major classes of inotropic agents currently used in infants include cardiac glycosides, β-adrenergic agonists and phosphodiesterase inhibitors. In every case, important developmental differences influence the responses to drugs from among these classes. For example, age-related changes occur in β-adrenergic receptor/effector coupling, G protein distribution, adenylyl cyclase activity/isoform expression, cAMP-dependent protein kinase activity, and expression and distribution of cyclic nucleotide phosphodiesterases and protein phosphatases. Little is known regarding the determinants of the maturational changes in responses to cardiac glycosides (such as digoxin). Nonetheless, these drugs are widely used in the neonatal population, even though documentation of their efficacy and safety is inadequate.